You are here
Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study
Lancet HIV 2015; 2: e127–36
Refers to article:
FLAMINGO: still in the pink?
The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks.
FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was –12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov , number NCT01449929 .
Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7–20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%]vs32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir groupvs57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%]vs34/242 [14%]), and headache (17/242 [7%]vs12/242 [5%]).
Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients.
ViiV Healthcare and Shionogi & Co.
For nearly two decades, government and agency guidelines for treatment-naive patients with HIV/AIDS have recommended the use of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third antiretroviral drug from one of three drug classes—a non-nucleoside reverse transcriptase inhibitor (NNRTI), a ritonavir-boosted protease inhibitor, or an integrase inhibitor.1, 2, 3, and 4Within such recommendations, boosted protease inhibitor regimens might be preferred as a first-line treatment because of their antiviral potency and their infrequent selection for resistance-associated mutations, thus preserving future treatment options. 5 However, limitations of boosted protease inhibitors include increased dyslipidaemia and interactions with other drugs metabolised by cytochrome P450. 6 Raltegravir, the first approved HIV integrase inhibitor, is effective and well tolerated but needs to be taken twice per day. 7 Elvitegravir, another integrase inhibitor, must be taken with food and needs pharmacological boosting, which can lead to clinically important drug–drug interactions.8, 9, and 10
Dolutegravir is an integrase inhibitor approved in several countries for once-daily dosing without the need for pharmacokinetic boosting and has a profile that reduces the potential for frequent drug interactions or food effect.11 and 12Two phase 3 studies have compared dolutegravir to an integrase inhibitor or NNRTI in treatment-naive patients. In SPRING-2,13 and 14once-daily dolutegravir was not inferior to twice-daily raltegravir with respect to the primary endpoint (proportion of participants with HIV-1 RNA <50 copies per mL) and showed similar safety and tolerability at 96 weeks. In SINGLE,15 and 16dolutegravir plus abacavir and lamivudine was statistically superior to combination treatment with efavirenz, tenofovir, and emtricitabine for the proportion of participants with HIV RNA less than 50 copies per mL at 96 weeks. Additionally, treatment-naive patients treated with dolutegravir did not develop any resistance-associated mutations in integrase or reverse transcriptase, whereas such mutations to both the NRTI backbone drugs and integrase inhibitors or NNRTIs developed in comparator treatment groups (ie, with raltegravir and combined efavirenz, tenofovir, and emtricitabine).
Evidence before this study
We searched PubMed on Feb 9, 2015, with combinations of the terms “integrase strand transfer inhibitor”, “integrase inhibitor”, “protease inhibitor (PI)”, “ritonavir”, “darunavir”, “efavirenz”, “superior”, “noninferior”, and “boosted”, with no restrictions on language. Integrase strand transfer inhibitor (INSTI) can be used in potent and well-tolerated first-line treatment regimens for HIV-infected individuals. The US Department of Health and Human Services and International AIDS Society USA Panel 2014 treatment guidelines recommended dolutegravir with either combined abacavir and lamivudine or combined tenofovir and emtricitabine for HIV-infected, treatment-naive individuals. Indeed, dolutegravir-based regimens are non-inferior or even superior to other recommended first-line regimens, including raltegravir, efavirenz, or combined darunavir and ritonavir-based regimens. The following INSTI-based treatment regimens are recommended for initial treatment (irrespective of pretreatment HIV-1 RNA loads): dolutegravir plus combined abacavir and lamivudine or combined tenofovir and emtricitabine; combined elvitegravir, cobicistat, tenofovir, and emtricitabine; and raltegravir plus combined tenofovir and emtricitabine.
Implications of all the available evidence
The FLAMINGO results at 96 weeks support dolutegravir 50 mg once daily in combination treatment with either abacavir and lamivudine or tenofovir and emtricitabine for management of HIV infection in treatment-naive patients and provide additional evidence for durable efficacy, tolerability, and a unique resistance profile within INSTIs. Dolutegravir offers clinical advantages over the earlier approved INSTIs raltegravir and elvitegravir because it is taken once per day, does not require a pharmacokinetic boosting drug, and has shown a high barrier for resistance-associated mutations in multiple studies. Triumeq (dolutegravir 50 mg, lamivudine 300 mg, and abacavir 600 mg) has been approved in the USA and in Europe as a once-daily single-pill regimen for the treatment of HIV-1 infection and represents, therefore, a new convenient regimen for treatment of HIV-infected individuals.
Added value of this study
The 96 week results of FLAMINGO offer a long-term comparison between the second-generation INSTI dolutegravir and the boosted protease inhibitor regimen of darunavir plus ritonavir. The results are consistent with results at 48 weeks, confirming the superior virological potency of dolutegravir compared with the protease inhibitor regimen with investigator-selected combined tenofovir and emtricitabine or combined abacavir and lamivudine in an HIV-1-infected, treatment-naive population. Virological non-response was rare (<10%) for the dolutegravir group with differences between regimens primarily caused by larger differences in patients with high viral load at baseline and moderate differences in tolerability. No treatment-emergent primary INSTI or nucleoside reverse transcriptase inhibitor resistance mutations were reported in the dolutegravir group, nor were treatment-emergent primary protease inhibitior or NRTI resistance mutations reported in the darunavir plus ritonavir group.
Because regimens based on protease inhibitors are unlikely to lead to the development of resistance-associated mutations, we did this phase 3b study to assess the efficacy, safety, and tolerability of dolutegravir versus a guideline-recommended boosted protease inhibitor-based regimen (darunavir plus ritonavir), in combination with two widely recommended NRTI backbones (combined tenofovir and emtricitabine or combined abacavir and lamivudine), as first-line treatment for treatment-naive adults with HIV-1 infection. The primary analysis of FLAMINGO at 48 weeks 17 showed that a significantly higher proportion of patients taking dolutegravir once daily (217 [90%] of 242 patients) than those taking darunavir plus ritonavir once daily (200 [83%] of 242), reached the primary endpoint (HIV-1 RNA <50 copies per mL), with similar safety and tolerability. Here, we report efficacy and safety data from the analysis of FLAMINGO at 96 weeks.
Study design and participants
FLAMINGO was a 96 week, phase 3b, randomised, open-label, active-controlled, parallel-group, non-inferiority study done at 64 research centres in France, Germany, Italy, Puerto Rico, Romania, Russia, Spain, Switzerland, and the USA. Eligible patients (aged ≥18 years) had plasma HIV-1 RNA of at least 1000 copies per mL, no previous antiretroviral treatment, and no evidence of primary viral resistance according to International AIDS Society 2013 guidelines. 18 The methods and eligibility criteria have been published. 17 Ethics committee approval was obtained at all participating centres in accordance with the principles of the Declaration of Helsinki. Each participant gave written informed consent.
Randomisation and masking
Patients were randomly assigned (1:1) via a central interface to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily each in combination with investigator-selected NRTI backbones of coformulated tenofovir and emtricitabine, or coformulated abacavir and lamivudine (selected before randomisation). The study statistician generated the randomisation list by computer. We stratified patients by viral load (≤100 000 or >100 000 HIV-1 RNA copies per mL) as predefined in the study protocol.
We defined virological failure as two consecutive plasma HIV-1 RNA values of more than 200 copies per mL at week 24 or later, confirmed by repeat testing within 2–4 weeks. Patients with confirmed virological failure were tested for virological resistance and withdrawn from the study. After 24 weeks, patients with confirmed 50–200 copies per mL of HIV-1 RNA could continue in the study on the basis of investigator discretion and local guidelines. Participants randomly assigned to receive dolutegravir and who successfully completed 96 weeks of treatment continued to have access to dolutegravir until either it was locally approved and commercially available, the patient no longer derived clinical benefit, or the patient discontinued. Participants assigned to receive dolutegravir were considered to have completed the study at week 96 if they chose not to participate in the extension phase. Participants in the extension phase completed the study when they transitioned to commercially available dolutegravir. Participants assigned to receive darunavir plus ritonavir were considered to have successfully completed the study at their week 96 visit.
We analysed viral genotype (reverse transcriptase and protease) centrally by Quest Diagnostics (Valencia, CA, USA) at screening. At time of confirmed virological failure, we did genotypic and phenotypic analyses (reverse transcriptase, protease, and integrase) of plasma samples from baseline and suspected virological failure for all patients with protocol-defined virological failure. We used GenoSure, Standard Phenosense, GeneSeq Integrase, and PhenoSense Integrase assays (Monogram Biosciences, San Francisco, CA, USA).
A pre-specified secondary endpoint of FLAMINGO was an analysis at 96 weeks of the proportion of participants with less than 50 copies per mL of HIV-1 RNA according to the US Food and Drug Administration (FDA) snapshot algorithm. Additional endpoints assessed at 96 weeks were tolerability and long-term safety, effects on lipids, CD4 and CD8 cell counts, health outcomes (Symptom Distress Module, EuroQol five dimension, HIV Treatment Satisfaction Questionnaire), and effects of patients' characteristics on virological response. 17
All analyses presented here were prespecified. The analyses were done for the modified intention-to-treat exposed or modified safety population, consisting of randomly assigned patients who received at least one dose of study drug from sites that complied with good clinical practice. The non-inferiority margin was –12%. To assess the effect of protocol deviations, we repeated the primary analyses for the per-protocol population (consisting of the modified intention-to-treat exposed population, excluding patients with a protocol deviation that met prespecified criteria). If the per-protocol and modified intention-to-treat exposed analyses showed non-inferiority and the lower end of the 95% CI for the modified intention-to-treat exposed analysis was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. The adjusted difference in proportions was based on a stratified analysis with Cochran-Mantel-Haenszel weights for baseline HIV-1 RNA viral load and investigator-selected backbone dual NRTIs. The protocol-defined genotypic and phenotypic virological failure populations consisted of all participants in the modified intention-to-treat exposed population with available on-treatment genotypic or phenotypic resistance data, respectively, at the time of protocol-defined virological failure.
Role of the funding source
The funders participated in study design. ViiV Healthcare participated in data collection, data analysis, data interpretation, and reviewed the report. All authors had full access to the data and are responsible for the veracity and completeness of the data reported. The corresponding author had final responsibility for the decision to submit for publication.
As of Feb 26, 2015, the study is ongoing with an extension phase; results presented here are for week 96 (data cutoff April 2, 2014). We screened 595 patients, of whom 488 were randomly assigned (243 to receive dolutegravir and 245 ritonavir-boosted darunavir). 485 patents received at least one dose of study drug, and 484 were analysed ( figure 1 ). Baseline demographics and disease characteristics were balanced between treatment groups and have been published previously. 17 61 (25%) of 242 patients in each group had a high viral load (HIV-1 RNA >100 000 copies per mL) at baseline. HIV-1 subtypes were similar in each group, with subtype B predominant (374/432 patients [87%]; data not available for 52 patients). Subtypes F1 and A1 were the next most common (20/432 [5%] each), and various subtypes, including AG, C, AE, CPX, and G, were detected in a small percentage of patients (≤2% each). Background NRTI treatment was similar between groups at baseline, with 163 (67%) of 242 patients in the dolutegravir group and 162 (67%) of 242 in the ritonavir-boosted darunavir group receiving tenofovir and emtricitabine.
At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 patients in the ritonavir-boosted darunavir group had HIV-1 RNA of less than 50 copies per mL ( table 1 ). Because the lower end of the 95% CI for the adjusted treatment difference from the efficacy analysis (4·7%) was above both –12% and 0%, dolutegravir was deemed both non-inferior and superior (p=0·002) to ritonavir-boosted darunavir at 96 weeks ( table 1 , figure 2 ). The results were driven by both the increase in the proportion of patients with HIV-1 RNA not below the threshold and rates of non-response because of lack of virological data in the ritonavir-boosted darunavir group, including participants who discontinued because of protocol deviation, loss to follow-up, and withdrawal of consent ( table 1 , figure 1 ). Virological non-response was more common at 96 weeks than at 48 weeks, particularly in the protease inhibitor group (19/242 [8%] at 48 weeksvs15/242 [6%] at 96 weeks in the dolutegravir group, 28/242 [12%]vs18/242 [7%] in the darunavir plus ritonavir group). In the per-protocol analysis, 194 (83%) of 234 patients in the dolutegravir group and 159 (70%) of 227 in the darunavir plus ritonavir group had less than 50 copies per mL plasma HIV-1 RNA at 96 weeks (adjusted difference in proportion 12·9, 95% CI 5·3–20·6).
|Dolutegravir 50 mg once daily (n=242)||Darunavir 800 mg plus ritonavir 100 mg once daily (n=242)|
|Week 48 *||Week 96||Week 48 *||Week 96|
|Virological success||217 (90%)||194 (80%)||200 (83%)||164 (68%)|
|Difference in proportion (95% CI; success)||7·0 (0·9–13·1)||12·4 (4·7–20·1)||··||··|
|Adjusted difference in proportion (95% CI; success) †||7·1(0·9–13·2) ‡||12·4(4·7–20·2) §||··||··|
|Virological non-response||15 (6%)||19 (8%)||18 (7%)||28 (12%)|
|Data in window not <50 copies per mL||6 (2%)||8 (3%)||11 (5%)||17 (7%)|
|Discontinued because of lack of efficacy||1 (<1%)||2 (1%)||1 (<1%)||3 (1%)|
|Discontinued for other reason while not <50 copies per mL||3 (1%)||3 (1%)||5 (2%)||6 (2%)|
|Change in antiretroviral therapy||5 (2%)||6 (2%)||1 (<1%)||2 (1%)|
|No virological data||10 (4%)||29 (12%)||24 (10%)||50 (21%)|
|Discontinued because of adverse event or death||3 (1%)||5 (2%)||9 (4%)||13 (5%)|
|Discontinued for other reasons ¶||6 (2%)||19 (8%)||11 (5%)||29 (12%)|
|Missing data during window but on study||1 (<1%)||5 (2%)||4 (2%)||8 (3%)|
* Week 48 data have been previously reported. 17
† Cochran-Mantel-Haenszel analysis stratified by baseline plasma HIV-1 RNA (≤100 000 copies per mL vs >100 000 copies per mL) and baseline background dual nucleoside reverse transcriptase inhibitor treatment (combined abacavir and lamivudine vs combined tenofovir and emtricitabine).
‡ Test for superiority p=0·025.
§ Test for superiority p=0·002.
¶ Including protocol deviation, loss to follow-up, and withdrawal of consent.
Data are number (%) unless otherwise indicated.
At 96 weeks, the efficacy of dolutegravir compared favourably with that of darunavir plus ritonavir across demographic and baseline characteristic subgroups, including ethnic origin, sex, and age ( figure 3 ), although the study was not powered to detect interactions by subgroup. Generally, the virological response rate at 96 weeks favoured the dolutegravir group, irrespective of baseline viral load, CD4 cell count, or background dual NRTI ( figure 2 , table 2 ). The greatest difference in responses between subgroups was for patients with a high viral load ( table 2 ). The treatment difference across high and low baseline HIV-1 RNA was not homogeneous (p=0·014). In the dolutegravir group, a similar proportion of patients with high and low baseline viral loads responded to treatment, whereas in the darunivir plus ritonavir group, patients with a high viral load at baseline had a lower response rate than did those with low viral load at baseline ( table 2 ).
|Responders||Unadjusted difference in proportion (95% CI)|
|Dolutegravir 50 mg once daily||Darunavir 800 mg plus ritonavir 100 mg once daily|
|Baseline plasma HIV-1 RNA *|
|≤100 000 copies per mL||144/181 (80%)||132/181 (73%)||6·6 (–2·1 to 15·4)|
|>100 000 copies per mL||50/61 (82%)||32/61 (52%)||29·5 (13·7 to 45·3)|
|Background dual NRTI treatment †|
|Combined abacavir and lamivudine||65/79 (82%)||60/80 (75%)||7·3 (–5·4 to 20·0)|
|Combined tenofovir and emtricitabine||129/163 (79%)||104/162 (64%)||14·9 (5·3 to 24·6)|
|Baseline CD4 cell count|
|<200 cells per μL||18/23 (78%)||14/24 (58%)||19·9 (–6·0 to 45·9)|
|200–350 cells per μL||60/73 (82%)||36/51 (71%)||11·6 (–3·7 to 26·9)|
|>350 cells per μL||116/146 (79%)||114/167 (68%)||11·2 (1·6 to 20·8)|
|Kaplan-Meier proportion without failure (%)|
|TRDF ‡||97·9%||94·7%||3·2 (–0·3 to 6·7) ¶|
|ERDF §||98·7%||98·1%||0·6 (–1·7 to 2·9) ¶|
* Test for homogeneity p=0·014 (one-sided p value from weighted least squares χ2 statistic).
† Test of homogeneity p=0·349 (one-sided p value from weighted least squares χ2 statistic).
‡ Protocol-defined virological failure or withdrawal because of drug-related adverse event, safety stopping criteria, or lack of efficacy.
§ Protocol-defined virological failure or withdrawal because of lack of efficacy.
¶ Based on Greenwood's formula.
Data are n/N (%) unless otherwise indicated. We used p≤0·10 to indicate significant heterogeneity in the difference in proportions of each analysis stratum. NRTI=nucleoside reverse transcriptase inhibitor. PDVF=protocol-defined virological failure. TRDF=treatment-related discontinuation failure. ERDF=efficacy-related discontinuation failure.
Differences in treatment response for patients in the high viral load stratum were attributed both to virological non-response (6/61 [10%] patients in the dolutegravir groupvs16/61 [26%] in the darunavir plus ritonavir group) and for non-virological reasons, including discontinuations for adverse events, deaths, other reasons, or for missing data (5/61 [8%]vs13/61 [21%]). Differences in virological responses between and within treatment groups remained when baseline viral load strata were further subdivided by background NRTI, although each subgroup has few participants ( appendix p 3 ). The proportion of responders based on a threshold of 400 copies per mL (snapshot) also was summarised by visit. At 96 weeks, this analysis supported the primary results with 202 (83%) of 242 patients in the dolutegravir group and 180 (74%) of 242 in the darunavir plus ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Table 2 shows Kaplan-Meier estimates of the proportion of patients without failure related to treatment or efficacy. Median change of CD4 count from baseline to 96 weeks was 260 cells per μL (IQR 185–400) in the dolutegravir group and 250 cells per μL (IQR 130–400) in the darunavir plus ritonavir group.
Two patients (1%) in the dolutegravir group and four (2%) in the darunavir plus ritonavir group had protocol-defined virological failure at 96 weeks. Two of these cases (in the darunivir plus ritonavir group) occurred after 48 weeks. The six patients with protocol-defined virological failure were evenly divided between high and low viral load strata at baseline (one for dolutegravir and two for darunavir plus ritonavir in each stratum) and included one patient in the dolutegravir group with a very high viral load at baseline (6·02 log10copies per mL). We recorded no treatment-emergent primary integrase inhibitor, protease inhibitor, or NRTI resistance mutations.
Tolerability and safety were much the same in each group ( table 3 ). Of the commonly reported clinical adverse events, diarrhoea was more common in the darunavir plus ritonavir group than in the dolutegravir group, whereas headache was more common in the dolutegravir group than in the darunavir plus ritonavir group. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir groupvs57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%]vs34/242 [14%]), and headache (17/242 [7%]vs12/242 [5%]). Although few adverse events resulted in discontinuation from the study or discontinuation of study drug in either group, more patients in the darunavir plus ritonavir group than in the dolutegravir group discontinued because of adverse events (15/242 [6%]vs7/242 [3%]; appendix p 4 ). No other individual adverse event led to withdrawal for more than one patient, with the exceptions of diarrhoea, nausea, rash, and increases in alanine aminotransferase and aspartate aminotransferase concentration, which were each given as reasons by two patients receiving darunavir plus ritonavir. Few withdrawals because of adverse events occurred after 48 weeks (three for dolutegravir and four for darunavir plus ritonavir; figure 1 ).
|Dolutegravir 50 mg once daily (n=242)||Darunavir 800 mg plus ritonavir 100 mg once daily (n=242)|
|Any event||222 (92%)||217 (90%)|
|Diarrhoea||44 (18%)||74 (31%)|
|Nausea||40 (17%)||48 (20%)|
|Headache||40 (17%)||26 (11%)|
|Nasopharyngitis||28 (12%)||25 (10%)|
|Upper respiratory tract infection||16 (7%)||27 (11%)|
|Insomnia||19 (8%)||16 (7%)|
|Cough||18 (7%)||19 (8%)|
|Pyrexia||16 (7%)||16 (7%)|
|Vomiting||15 (6%)||17 (7%)|
|Back pain||14 (6%)||17 (7%)|
|Fatigue||15 (6%)||14 (6%)|
|Rash||13 (5%)||17 (7%)|
|Bronchitis||11 (5%)||18 (7%)|
|Dizziness||14 (6%)||13 (5%)|
|Gastroenteritis||13 (5%)||14 (6%)|
|Pharyngitis||11 (5%)||14 (6%)|
|Arthralgia||10 (4%)||16 (7%)|
|Depression||15 (6%)||9 (4%)|
|Abdominal pain||13 (5%)||12 (5%)|
|Syphilis||11 (5%)||12 (5%)|
|Anxiety||13 (5%)||9 (4%)|
|Sinusitis||9 (4%)||13 (5%)|
|Myalgia||7 (3%)||12 (5%)|
|Constipation||13 (5%)||6 (2%)|
|Asthenia||5 (2%)||11 (5%)|
|Flatulence||4 (2%)||11 (5%)|
|Influenza||4 (2%)||11 (5%)|
Data are number of patients (%).
At 96 weeks, the incidence of serious adverse events was higher in the dolutegravir group (36/242 [15%]) than in the darunavir plus ritonavir group (21/242 [9%]), as in the analysis at 48 weeks. 17 Since the analysis at 48 weeks, ten patients reported 14 serious adverse events in the dolutegravir group and eight patients reported nine serious adverse events in the darunavir plus ritonavir group ( appendix p 5–6 ). Each type of event was reported in less than 1% of particpants in each group, except for attempted suicide. In the dolutegravir group, three serious adverse events (tendon rupture, polyarthritis [both after 48 weeks], and suicide attempt) were deemed possibly drug related; none in the darunavir plus ritonavir group were classed as drug related.
Between baseline and 48 weeks, three patients in the dolutegravir group attempted suicide with one of these events considered possibly related to study drug; no suicide attempts occurred in the darunavir plus ritonavir group. All of these patients had a history of suicidal ideation. A fourth participant in the dolutegravir group died by suicide after 48 weeks. This patient had a history of previous suicide attempt and bipolar depression. The investigator concluded that there was no reasonable possibility that suicide was related to dolutegravir. One participant treated with darunavir plus ritonavir developed severe grade 3 depression and had a suicide attempt accompanying LSD intoxication. The final diagnosis was recorded as “LSD intoxication”; thus, these events were not counted as “suicide attempt”. The investigator concluded that there was no reasonable possibility the events were caused by study drug. An assessment of medical conditions at baseline showed that 16 (7%) of 242 patients randomly assigned to dolutegravir and nine (4%) of 242 randomly assigned to darunavir plus ritonavir had past suicidal ideations, and one participant in the dolutegravir group had current suicidal ideation.
Lipid profiles were favourable for the dolutegravir group compared with the darunavir plus ritonavir group. Mean increase in fasting LDL cholesterol at week 96 was significantly higher in the darunavir plus ritonavir group than in the dolutegravir group (adjusted mean difference –0·33 mmol/L, 95% CI –0·45 to –0·21; p<0·0001). At 96 weeks, mean total cholesterol and triglycerides had changed little from baseline in the dolutegravir group, with greater increases in the darunavir plus ritonavir group than in the dolutegravir group ( table 4 ). Mean total cholesterol:HDL cholesterol ratio increased in both groups ( table 4 ). More post-baseline emergent laboratory abnormalities occurred in the darunavir plus ritonavir group than in the dolutegravir group for total cholesterol (111/242 [46%]vs43/242 [18%]) and LDL cholesterol (88/242 [36%]vs39/242 [16%]). Consistent with findings at 48 weeks, 17 the incidence of grade 2 or higher fasting LDL laboratory abnormalities by week 96 was significantly higher in the darunavir plus ritonavir group (48/220 [22%]) than in the dolutegravir group (15/220 [7%]; p<0·0001). Few post-baseline emergent triglyceride laboratory toxic effects occurred in either group: 12 (5%) of 242 patients in the darunavir plus ritonavir group compared with four (2%) of 242 in the dolutegravir group. Of patients who started the study with LDL concentrations based on National College Education Program (NCEP) categorisation at optimum or near/above optimum categories (<3·36 mmol/L), the number of patients who migrated to the borderline high/high/very high (≥3·36 mmol/L) categories during the study was 34 (18%) of 185 in the dolutegravir group and 69 (38%) of 181 in the darunavir plus ritonavir group. We identified no clinically significant patterns of change in vital signs or electrocardiograms in either group (data not shown).
|Dolutegravir group (n=242)||Darunavir plus ritonavir group (n=242)|
|n||Absolute mean (SD)||n||Absolute mean (SD)|
|Total cholesterol (mmol/L)|
|Baseline||207||4·08 (0·86)||215||4·20 (0·90)|
|Week 48||199||4·17 (0·86)||192||4·86 (1·15)|
|Week 96||183||4·28 (0·87)||164||5·01 (1·09)|
|LDL cholesterol (mmol/L)|
|Baseline||207||2·36 (0·74)||215||2·47 (0·76)|
|Week 48||199||2·42 (0·72)||192||2·85 (0·95)|
|Week 96||183||2·52 (0·75)||164||3·01 (0·87)|
|HDL cholesterol (mmol/L)|
|Baseline||207||1·14 (0·34)||215||1·13 (0·32)|
|Week 48||199||1·18 (0·39)||192||1·20 (0·37)|
|Week 96||183||1·19 (0·40)||164||1·24 (0·40)|
|Total cholesterol:HDL cholesterol ratio|
|Baseline||222||3·85 (1·20)||227||4·06 (1·67)|
|Week 48||215||3·84 (1·36)||202||4·43 (1·78)|
|Week 96||196||3·96 (1·60)||172||4·38 (1·41)|
|Baseline||207||1·29 (0·75)||215||1·33 (0·75)|
|Week 48||200||1·25 (0·83)||192||1·80 (1·54)|
|Week 96||184||1·26 (0·80)||164||1·70 (1·13)|
From baseline to 96 weeks, 13 (5%) of 242 patients in the dolutegravir group had alanine aminotransferase concentrations at least three times the upper limit of normal compared with eight (3%) of 242 patients in the darunavir plus ritonavir group; mean alanine aminotransferase, aspartate aminotransferase, or total bilirubin did not increase in either group (data not shown). 29 (12%) of 242 participants in the dolutegravir group versus 15 (6%) of 242 in the darunavir plus ritonavir group met at least one FDA hepatobiliary laboratory abnormality criterion at any visit after baseline. Two (<1%) versus four (2%) met the protocol liver stopping criteria. No liver events occurred in either group with concomitant clinically significant enzyme and bilirubin increases (data not shown). The increase in mean alkaline phosphatase at 48 weeks 17 remained stable through to 96 weeks (dolutegravir 7·9 IU/L; darunavir plus ritonavir 10·1 IU/L). All participants with significant liver chemistry increases had alternative diagnoses such as acute hepatitis C or concomitant prescription or illegal drug use.
Participants receiving dolutegravir had mild increases in serum creatinine evident by week 2 that were stable up to 48 weeks. 17 At 96 weeks, creatinine concentrations remained stable in the dolutegravir group with smaller mean changes from baseline in the darunavir plus ritonavir group (3·9 μmol/L [SD 20·7]vs15·4 μmol/L [10·3]; appendix p 1–2 ). Between baseline and 96 weeks, 16 (7%) of 242 participants in the dolutegravir group versus one (<1%) of 242 in the darunavir plus ritonavir group had post-baseline emergent grade 1 creatinine increase, and two patients in the dolutegravir group and one in the darunavir plus ritonavir group had grade 2 increases. No participants had grade 3 or grade 4 increases. Median urine albumin:creatinine ratios were much the same in both groups at baseline and remained stable up to 96 weeks (data not shown). More patients had grade 4 increases of creatine phosphokinase in the dolutegravir group than in the darunavir plus ritonavir group (9/242 [4%]vs5/242 [2%]). In all these cases, creatine phosphokinase concentrations oscillated with time, and the increases were transient changes from baseline that did not follow a clear temporal relationship with the start of study drug treatment (data not shown).
Health outcomes at 96 weeks were consistent with those reported for 48 weeks. 17 Symptom Distress Module Bother Score or the EuroQol five dimension 19 utility and thermometer scores did not differ significantly between groups (data not shown). However, for the HIV Treatment Satisfaction Questionnaire,20 and 21participants in the dolutegravir group had significantly higher mean total scores at 96 weeks than did patients in the darunavir plus ritonavir group (56·6 [SD 4·74]vs54·5 [SD 7·03], p=0·004), as well as significantly higher mean scores in the lifestyle/ease subscore (27·6 [SD 3·42]vs26·6 [SD 4·19], p=0·031) and the convenience item score (5·7 [SD 0·73]vs5·3 [SD 1·03], p<0·0001).
The results of the secondary analysis of FLAMINGO at 96 weeks support those of the primary analysis at 48 weeks, because dolutegravir remained statistically superior to darunavir plus ritonavir for the proportion of participants with plasma HIV-1 less than 50 copies per mL. The incidence of virological non-response between 48 and 96 weeks was comparable with rates reported in other randomised trials of integrase inhibitors and protease inhibitors for treatment-naive patients with HIV-1.14, 22, and 23The safety profile of dolutegravir was similar to that of darunavir plus ritonavir, and virological non-response was low with no treatment-emergent resistance in either treatment group.
Subgroup analyses within stratification for baseline HIV RNA (≤100 000 or >100 000 copies per mL) and NTRI backbone supported the overall difference between treatment groups. Because response rates in the dolutegravir group were similar across the HIV RNA strata, the differences between treatment groups were driven by a lower response rate among patients in the darunavir plus ritonavir group who were in the high viral load stratum. Additionally, virological failure in patients with low baseline viral load occurred in similar proportions in each treatment group. The lower treatment response reported in the darunavir plus ritonavir group for patients with high viral loads at baseline was primarily caused by greater rates of virological non-response. Additional preplanned subgroup analysis, including race, sex, age, baseline disease category, baseline CD4 count, and country, generally supported the primary results and suggest that dolutegravir is efficacious across demographic and baseline characteristics. Because each stratum and subgroup contained few participants, these results should be interpreted with caution.
Decreases in viral load and mean increases in CD4 counts between baseline and 96 weeks in FLAMINGO are consistent with results reported for dolutegravir in the phase 3, double-blind SPRING-2 study, 14 comparing dolutegravir 50 mg once daily with raltegravir 400 mg twice daily plus investigator-selected tenofovir and emtricitabine or abacavir and lamivudine for 96 weeks. Results of the AIDS Clinical Trials Group's A5257 trial, a phase 3, open-label study, 7 showed that raltegravir was significantly superior to ritonavir-boosted atazanavir or ritonavir-boosted darunavir with FDA snapshot, similar to the results of FLAMINGO. Increases in lipid concentrations through to 96 weeks for darunavir plus ritonavir treatment in FLAMINGO are consistent with the results from the ACTG A5257 and ARTEMIS 23 studies.
The investigators of the ARTEMIS trial, an open-label, phase 3 study of treatment-naive patients comparing darunavir 800 mg and ritonavir 100 mg once daily with lopinavir 800 mg and ritonavir 200 mg, reported differences in virological responses between patients treated with protease inhibitors who had high and low baseline viral loads. Virological response rates after 96 weeks of treatment with ritonavir-boosted darunavir were slightly higher in ARTEMIS than in FLAMINGO and ACTG A5257. The greater virological response rate in the ARTEMIS study might be a result of the inclusion criteria, which required a baseline viral load of at least 5000 copies per mL, compared with 1000 copies per mL or more for FLAMINGO and ACTG A5257.
Another important secondary objective in FLAMINGO was tolerability and long-term safety. The treatments were comparable for the safety analysis at 96 weeks, with an overall similar rate of adverse events, including key laboratory variables. The safety profile was consistent with current labelling for darunavir, 24 dolutegravir, 11 and combined dolutegravir, abacavir, and lamivudine. 25 Similar numbers of patients in each group had insomnia; this rate was less than was reported in SINGLE at 96 weeks, in which patients received dolutegravir 50 mg and combined abacavir and lamivudine once daily. 16 In FLAMINGO, patients in the dolutegravir group reported serious adverse events related to, or relevant to, psychiatric disorders, particularly suicidal ideation or behaviour. These patients had confounding risk factors, including medical history. Additionally, a greater proportion of patients in the dolutegravir group than in the darunavir and ritonavir group reported past suicidal ideation at baseline, which could have led to an imbalance in adverse events reported within the psychiatric system organ class. The rate of suicidal activity in the dolutegravir group in FLAMINGO was the same or lower than the rate in the comparator arm in other phase 3 pivotal studies of dolutegravir.14 and 15
One limitation to the assessment of safety was the open-label design, which might have affected patient retention, reporting of adverse events, investigator assessment of relatedness of adverse events to study drug, and patient-reported health outcomes. Because patient retention included in the FDA snapshot algorithm partly determines virological success rates, any effects of an open-label design on discontinuation, including protocol deviation, loss to follow-up, or withdrawal of consent, had the potential to affect the difference in the reported virological response rate. Although a similar number of patients in each group withdrew consent at 48 weeks, more withdrew consent in the darunavir plus ritonavir group by 96 weeks.
Small increases in serum creatinine concentration in the dolutegravir group are consistent with previous findings and not regarded as clinically significant.26 and 27Creatinine increases are attributable to the inhibition of the renal transporter organic cation transporter 2, as reported with other drugs including trimethoprim and cimetidine,28 and 29which decrease tubular secretion of creatinine and thereby increase concentrations of serum creatinine without affecting glomerular filtration. 30 Few participants in either treatment group in our study had graded creatinine abnormalities, and none withdrew because of renal adverse events. Changes from low LDL concentrations at baseline to high concentrations by 96 weeks were more common in the darunavir plus ritonavir group than in the dolutegravir group. This finding might indicate that patients treated with darunavir plus ritonavir are more likely to need LDL-lowering drug treatment according to the NECP criteria, pending individual assessment of cardiovascular risks, than are patients treated with dolutegravir.
Few patients had protocol-defined virological failure between baseline and 96 weeks, including no new cases in the dolutegravir group after 48 weeks. The absence of treatment-emergent primary integrase inhibitor or NRTI resistance is consistent with studies such as SPRING-213 and 14and SINGLE,15 and 16in which dolutegravir, when given to treatment-naive patients along with dual NRTIs, had a robust resistance profile. These findings suggest a similar barrier to development of resistance for dolutegravir and boosted darunavir in treatment-naive patients. It has been established that treatment with dolutegravir and integrase inhibitors induces a rapid and robust virological response within 24 weeks. Results from FLAMINGO confirm that durable suppression of viral replication, at least similar to that obtained with a boosted protease-inhibitor-based regimen, after 96 weeks is achieved with treatment with dolutegravir 50 mg once daily, when administered with backbone dual NRTI treatment.
This online publication has been corrected. The corrected version first appeared at thelancet.com on March 13, 2015
J-MM participated in recruitment and follow-up of patients, critical review and discussion of the final study report, data collection and interpretation, drafting of the report, and had final responsibility for the decision to submit for publication. BC participated in conduct of the study, recruitment and follow-up of patients, data collection, interpretation, and writing. JvL participated in the design and conduct of the study, recruitment and follow-up of patients, critical review and discussion of the final study report, and drafting of the report. AL was a principal investigator and collected, analysed, and interpreted data and assisted in writing and reviewing the report. MC participated in conduct of the study, recruitment and follow-up of patients, data collection and interpretation, and report writing. KH was a principal investigator at an active site and assisted with enrolling patients, collecting and interpreting data, and contributing to writing and review of the report. VK was a principal investigator at an active site and assisted with enrolling patients, collecting and interpreting data, and contributed to writing and review of the report. NG contributed to data analysis and interpretation and writing of the report. CFdO was a medical reviewer of the study since development of the draft protocol and was the medical monitor for sites in North America and was the global medical monitor lead for PPD. He was also involved in medical review of the clinical study reports generated with the study data, and in the review of production of the report. CB participated in acquisition of data and clinical oversight of the study, analysis and interpretation of data, and drafting and revising the report.
France: M-A Khuong-Josses, J-M Molina, G Pialoux, F Raffi, J Reynes, P Yeni. Germany: W Kern, C Stephan, J Van Lunzen. Italy: A Antinori, A D'Arminio Monforte, G Di Perri, G Guaraldi, A Lazzarin. Puerto Rico: I Melendez-Rivera, J Morales Ramirez, J Santana-Bagur. Romania: D Duiculescu, L Preotescu, S Rugina. Russia: O Kozyrev, V Kulagin, V Pokrovskiy, A Shuldyakov, E Voronin. Spain: B Clotet, J Gatell, D Podzamczer, R Rubio, P Viciana. Switzerland: M Cavassini, J Fehr, H Furrer. USA: N Bellos, G Blick, I Brar, C Dietz, R Dretler, R Elion, J Eron, J Feinberg, G Georgescu, A Scribner, D Hagins, W Henry, C Martorell, C Mayer, L McCurdy, A Mills, M Murphy, C Newman, R Ortiz, G Pierone, A Rana, M Saag, P Shalit, G Simon, L Sloan, J Stephens, P Tebas, W Towner, M Tribble, D Warner, A Wilkin, B Young.
Declaration of interests
J-MM has participated in advisory boards for Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare and has received research grants from Gilead Sciences and Merck. BC has received research grants from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare and personal fees from Abbot and Janssen. JvL has received honoraria, served as an adviser, and received research funding from AbbVie, Bionor, Boehringer Ingelheim, Bristol-Myers Squibb, Genetic Immunity, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Roche, ViiV Healthcare, and Vision7. MC has served as an expert for AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck Sharp & Dohme; has received honoraria for such services; and has received unrestricted research grants from Bristol-Myers Squibb, Gilead Sciences, and Merck Sharp & Dohme. KH has received research support from Gilead Sciences and ViiV Healthcare. NG is an employee of GlaxoSmithKline. CFdO is as an employee of PPD and acted in the study as part of PPD's contractual relationship with GlaxoSmithKline. CB is an employee of and holds stock in GlaxoSmithKline. AL and VK declare no competing interests.
This work was funded by ViiV Healthcare and Shionogi & Co. We thank the study patients, and their families and caregivers for participation in the study. We also thank Krischan J Hudson for being lead medical writer, and Justin Koteff and Meredith MacPherson for editorial assistance during the development of this report.
- 1 WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. June, 2013.. http://www.who.int/hiv/pub/guidelines/arv2013/en/ (accessed Sept 12, 2014).
- 2 European AIDS Clinical Society. Guidelines for treatment of HIV-infected adults in Europe (version 7.1). November, 2014. http://www.eacsociety.org/files/guidelines_english_71_141204.pdf (accessed March 3, 2015).
- 3 HF Günthard, JA Aberg, JJ Eron, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society−USA panel. JAMA. 2014;312:410-425
- 4 US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. November, 2014. http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf (accessed Sept 9, 2014).
- 5 ES Daar, C Tierney, MA Fischl, et al., for the AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011;154:445-456 Crossref
- 6 JA Aberg, P Tebas, ET Overton, et al. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks. AIDS Res Hum Retroviruses. 2012;28:1184-1195 Crossref
- 7 JL Lennox, RJ Landovitz, HJ Ribaudo, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-471
- 8 E DeJesus, J Rockstroh, K Henry, et al., for the GS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379:2429-2438 Crossref
- 9 AR Zolopa, DS Berger, H Lampiris, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis. 2010;201:814-822 Crossref
- 10 R Schrijvers, Z Debyser. Quad's in it for antiretroviral therapy?. Lancet. 2012;379:2403-2405 Crossref
- 11 ViiV Healthcare. Tivicay: USA prescribing information (ViiV Healthcare, Research Triangle Park, 2013)
- 12 I Song, J Borland, S Chen, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012;56:1627-1629 Crossref
- 13 F Raffi, A Rachlis, HJ Stellbrink, et al., for the SPRING-2 Study Group. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381:735-743 Crossref
- 14 F Raffi, H Jaeger, E Quiros-Roldan, et al., for the extended SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13:927-935 Crossref
- 15 SL Walmsley, A Antela, N Clumeck, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369:1807-1818 Crossref
- 16 Walmsley S, Berenguer J, Khuong-Josses M, et al. Dolutegravir regimen statistically superior to efavirenz/tenofovir/emtricitabine: 96-week results from the SINGLE study (ING114467). 21st Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA; March 3–6, 2014. Abstract 543.
- 17 B Clotet, J Feinberg, J van Lunzen, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014;383:2222-2231
- 18 VA Johnson, V Calvez, HF Gunthard, et al. Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med. 2013;21:6-14
- 19 EuroQol Research Foundation. What is EQ-5D. http://www.euroqol.org (2013) (accessed Sept 9, 2014).
- 20 A Woodcock, C Bradley. Validation of the HIV treatment satisfaction questionnaire (HIVTSQ). Qual Life Res. 2001;10:517-531 Crossref
- 21 A Woodcock, C Bradley. Validation of the revised 10-item HIV Treatment Satisfaction Questionnaire status version and new change version. Value Health. 2006;9:320-333 Crossref
- 22 JL Lennox, E Dejesus, DS Berger, et al., for the STARTMRK Investigators. Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune Defic Syndr. 2010;55:39-48 Crossref
- 23 AM Mills, M Nelson, D Jayaweera, et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS. 2009;23:1679-1688 Crossref
- 24 Janssen Pharmaceuticals. Prezista: USA prescribing information (Janssen Pharmaceuticals, Titusville, 2013)
- 25 ViiV Healthcare. Triumeq: USA prescribing information (ViiV Healthcare, Research Triangle Park, 2014)
- 26 HJ Stellbrink, J Reynes, A Lazzarin, et al., for the SPRING-1 Team. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS. 2013;27:1771-1778 Crossref
- 27 J van Lunzen, F Maggiolo, JR Arribas, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12:111-118 Crossref
- 28 E Burgess, A Blair, K Krichman, RE Cutler. Inhibition of renal creatinine secretion by cimetidine in humans. Ren Physiol. 1982;5:27-30 Crossref
- 29 J Kastrup, P Petersen, R Bartram, JM Hansen. The effect of trimethoprim on serum creatinine. Br J Urol. 1985;57:265-268 Crossref
- 30 J Koteff, J Borland, S Chen, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol. 2013;75:990-996 Crossref
a University of Paris Diderot Paris 7, Sorbonne Paris Cité, INSERM U941, Department of Infectious Diseases, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
b Hospital Universitari Germans Trias i Pujol, HIV Unit, Irsicaixa Foundation, UAB, UVIC-UCC, Badalona, Catalonia, Spain
c University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg, Germany
d IRCCS San Raffaele Via Stamira d'Ancona, Department of Infectious Diseases, Milan, Italy
e Lausanne University Hospital, Infectious Disease Service, Lausanne, Switzerland
f Hennepin County Medical Center, Department of Medicine, Minneapolis, MN, USA
g Clinical Center for Prevention and Control of AIDS, Krasnodar, Russia
h GlaxoSmithKline, Clinical Statistics, Stockley Park, UK
i PPD, Pharmacovigilance, Morrisville, NC, USA
j GlaxoSmithKline, Infectious Diseases, Research Triangle Park, NC, USA
* Correspondence to: Prof Jean-Michel Molina, University of Paris Diderot Paris 7, Department of Infectious Diseases, Saint-Louis Hospital, INSERM U941, Paris, France
© 2015 Elsevier Ltd, All rights reserved.
Reprints Account Manager
T: +44 (0)20 7424 4221
The Lancet HIV is a monthly
online journal. For further
information on how to subscribe
please contact our
T: +44 (0) 1865 843077
F: +44 (0) 1865 843970
T: +1 (800) 462 6198
F: +1 (800) 327 9021
Elsevier España, S.L.U.
(A member of Elsevier)
Av. Josep Tarradellas, 20-30
Tel.: 932 000 711
Fax: 932 091 136
This e-print is distributed with the support of GSK.
© 2015 Elsevier Ltd. All rights reserved. This journal and the individual contributions contained in it are protected under copyright by Elsevier Ltd, and the following terms and conditions apply to their use.
Publication information The Lancet HIV (ISSN 2352-3018) is published monthly by Elsevier (The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK). Photocopying Single photocopies of single articles may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use.
Permissions may be sought directly from Elsevier Global Rights Department, The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK, tel: +1 215 239 3804 or +44 (0)1865 843830, fax: +44 (0)1865 853333, email email@example.com
In the USA, users may clear permissions and make payments through the Copyright Clearance Center Inc, 222 Rosewood Drive, Danvers, MA
01923, USA; tel: +1 (978) 7508400, fax: +1 (978) 646-8600.
Other countries may have a local reprographic rights agency for payments.
Derivative works Subscribers may reproduce tables of contents or prepare lists of articles including abstracts for internal circulation within their institutions. Permission of the Publisher is required for resale or distribution outside the institution.
Permission of the Publisher is required for all other derivative works, including compilations and translations.
Electronic storage or usage Permission of the Publisher is required to store or use electronically any material contained in this journal, including any article or part of an article.
Except as outlined above, no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission of the Publisher.
Address permissions requests to: Elsevier Health Sciences Rights Department, at the mail, fax, and email addresses noted above.
Notice No responsibility is assumed by Elsevier for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.
The views expressed in this journal are not necessarily those of the
Editor, the International Advisory Board, or Elsevier Ltd.